Maternal cortisol concentrations are normally increased by 2-3 fold in pregnancy. Maternal cortisol levels appear to affect fetal skeletal and visceral growth. Our previous data show reduced growth in fetuses of ewes with either increased or decreased maternal cortisol levels, consistent with clinical reports that either hypoadrenocorticism, Addison's disease, or hyperadrenocorticism, Cushing's syndrome, results in small for gestational age infants. In these studies we will use pregnant sheep in late gestation to test several hypotheses relating to effects of maternal cortisol on fetal growth and on maternal, fetal, and neonatal metabolism. Three groups of ewes will be used: 1) normal intact control ewes, 2) ewes that are adrenalectomized and replaced with cortisol to levels half that of normal pregnancy, but similar to those of normal nonpregnant ewes, 3) ewes infused with cortisol to double normal plasma concentrations relative to the control pregnant ewes. We propose two sets of studies to determine effects on both maternal and fetal physiology, and on neonatal physiology. We will test the hypothesis that reductions in maternal cortisol alter fetal growth and metabolism primarily by reducing maternal volume expansion, and the normal increases in maternal cardiac output and uteroplacental blood flow that are essential for acceleration of fetal growth in the late gestation, and secondarily, by reducing maternal food intake and maternal and fetal glucose concentrations. We also will test the related hypothesis that these changes result in a neonate with proportionate reduction in weight of fetal organs, reduced fat mass and reduced IGF-I expression in adipose tissue and liver. We will also test the hypothesis that fetal adrenal maturation will be slightly accelerated in these fetuses, resulting in slightly earlier delivery as compared to the control groups, and we will test the hypotheses that there will be an impaired insulin response to increases in glucose postnatally in the lambs born of ewes with relative hypoadrenocorticism. In parallel experiments, we will test the hypothesis that increases in maternal cortisol, similar to those produced by chronic stress, do not negatively impact uteroplacental blood flow, but result in reduction in skeletal growth by affects on IGF levels, and will cause organ-specific changes in organ growth and in growth-related genes in the viscera. We also will test the hypothesis that increased feeding in these ewes, in combination with increased maternal cortisol will result in increased maternal and fetal glucose concentrations, with increased adiposity, but reduced neonatal glucose and cortisol concentrations in the period immediately following birth, and reduced glucose tolerance in the first month of life. PUBLIC HEALTH RELEVANCE: Diseases associated with either excess or deficient maternal secretion of the adrenal hormone cortisol have been found to be associated with reduction in fetal growth. Excess secretion of cortisol due to maternal stress has also been suggested as a contributing factor in small for gestational age babies; however, little is known about how changes in maternal cortisol influence either maternal physiology or fetal growth and metabolism. These studies will improve our understanding of the role of the normal increase in maternal cortisol that occurs in healthy pregnancies and how increases or decreases impact both fetal and neonatal growth and metabolism.